10.1021/ol201139w r 2011 American Chemical SocietyPublished on Web 06/02/2011

ORGANICLETTERS

2011Vol. 13, No. 133384–3387

Highly Regioselective [3 þ 2] Annulationof Azomethine Imines with 1-AlkynylFischer Carbene Complexesto Functionalized N,N-BicyclicPyrazolidin-3-ones

Ning Luo,† Zhaoyan Zheng,† and Zhengkun Yu*,†,‡

Dalian Institute of Chemical Physics, Chinese Academy of Sciences (CAS), 457Zhongshan Road, Dalian, Liaoning 116023, P. R. China, and State Key Laboratory ofOrganometallic Chemistry, Shanghai Institute of Organic Chemistry, CAS, 354 FenglinRoad, Shanghai 200032, China

zkyu@dicp.ac.cn

Received April 29, 2011

ABSTRACT

The highly regioselective [3 þ 2] cycloaddition of azomethine imines to 1-alkynyl Fischer carbene complexes has been successfully realizedunder mild conditions. Oxidative demetalation of the newly formed pyrazolo-pyrazolone carbene complexes with pyridine-N-oxide or cericammonium nitrate efficiently afforded pyrazolo-pyrazolone derivatives as well as cycloprop-2-enone and trisubstituted 1H-pyrazoles in somecases, providing a novel route to versatile functionalized N,N-bicyclic pyrazolidin-3-ones.

N,N-Bicyclic pyrazolidin-3-ones, i.e., pyrazolo-pyrazo-lone derivatives, usually exhibit distinct bioactivity, andsome of them have attracted much attention in drugdevelopment.1 For example, tetrahydropyrazolo[1,2-a]pyrazolones have been studied as the analogs of penicillinand cephalosporin antibiotics over the past two decades

(Scheme 1).2,3 To date, construction of such aN,N-bicycliccore has become a challenging task in organic synthesis,and the most possible route to reach this goal seems to be1,3-dipolar cycloaddition of azomethine imines withalkynes.4 However, azomethine imines have been appliedwith limitations for synthetic purposes as comparedwith azomethine ylides and nitrones.5 Only by means of

†Dalian Institute of Chemical Physics.‡ Shanghai Institute of Organic Chemistry.(1) (a) Eicher, T.; Hauptmann, S.The Chemistry of Heterocycles, 2nd

ed.; Wiley-VCH: Weinheim, 2003. (b) Claramunt, R. M.; Elguero, J. Org.Proc. Prep. Int. 1991, 23, 273.

(2) (a) Jungheim, L. N.; Sigmund, S. K.; Fischer, J. W. TetrahedronLett. 1987, 28, 285. (b) Jungheim, L. N.; Sigmund, S. K. J. Org. Chem.1987, 52, 4007.

(3) (a) Panfil, I.; Urba�nczyk-Lipkowska, Z.; Suwi�nska, K.; Solecka,J.; Chmielewski, M. Tetrahedron 2002, 58, 1199. (b) Ternansky, R. J.;Draheim, S. E. J. Med. Chem. 1993, 36, 3219.

(4) Keller, M.; Sido, A. S. S.; Pale, P.; Sommer, J. Chem.;Eur. J.2009, 15, 2810.

(5) For selected recent reports, see: (a) Barroso, S.; Blay, G.; Mu~noz,M. C.; Pedro, J. R.Org. Lett. 2011, 13, 402. (b) Hashimoto, T.; Maeda,Y.; Omote,M.; Nakatsu, H.;Maruoka,K. J. Am. Chem. Soc. 2010, 132,4076. (c) Stanley, L. M.; Sibi, M. P. Chem. Rev. 2008, 108, 2887. (d)Pandey, G.; Banerjee, P.; Gadre, S. R. Chem. Rev. 2006, 106, 4484.

(6) (a) Su�arez, A.; Downey, C.W.; Fu,G. C. J. Am. Chem. Soc. 2005,127, 11244. (b) Shintani, R.; Fu, G. C. J. Am. Chem. Soc. 2003, 125,10778.

Org. Lett., Vol. 13, No. 13, 2011 3385

electron-poor terminal alkynes,6 enones,7 and benzynes,8

1,3-dipolar [3 þ 2] cycloadditions of azomethine iminescan occur, forming a less substituted N,N-bicyclic corethan that described in Scheme 1.2,6 Thus, exploration ofnew synthetic methods to functionalized N,N-bicyclicpyrazolidin-3-one derivatives is strongly desired.9 Fischercarbene complexes have been used as versatile buildingblocks in organic synthesis.10 The [3 þ 2] cycloaddition ofalkynyl Fischer carbene complexes withN-alkyl nitrones11

and azides12 was reported for the synthesis of N-hetero-cyclic compounds. Although Fischer carbene complexeshave been extensively applied to construct six-memberedrings via [4 þ 2] cycloaddition, their successful [3 þ 2]annulations to five-membered heterocycles have beenlimited to a few examples.10,13�16 In these 1,3-dipolarcycloaddition reactions, the metal pentacarbonyl moiety

of a Fischer carbene substrate usually accelerates thereaction and enhances the selectivity of the desired pro-duct. Recently, we disclosed [3 þ 2] cycloadditions of1-alkynyl Fischer carbene complexes with pyrazolinonesfor the preparation of N,N-bicyclic bimanes featuringstrong luminescence.15 Herein, we report the novel [3 þ 2]cycloaddition of azomethine imines (2) with internalalkynes, i.e., 1-alkynyl Fischer carbene complexes (1), tosynthesize potentially bioactive functionalized N,N-bicyc-lic pyrazolidin-3-one derivatives.The reaction of 1-alkynyl Fischer carbene complex 1a

with azomethine imine 2awas initially carried out under anitrogen atmosphere. At rt�50 �C, the reaction seldom

occurred in chloroform or benzene, whereas it under-went completion in THF within 2 h, forming a [3 þ 2]cycloaddition product, i.e., pyrazolo-pyrazolone 3a, in71% yield as the only product (Table 1, entry 1). In asimilar fashion, products 3b�g were isolated in 61�78%yields (entries 2�7). Using PhCONH-substituted azo-methine imines 2e�h, compounds 3h�k were collected in25�51%yields (entries 8�11). Fischer carbene complex 1awas much less reactive than 1b in the reactions withazomethine imines 2e�h, resulting in no measurableamount of the target products. With 1-alkynyl Fischercarbene complexes 1c�f, the same type of [3þ 2] cycload-dition products 3l�o were obtained in 60�86% yields

Table 1. [3 þ 2] Cycloaddition of Azomethine Imines 2with 1a

entry M, R (1) R1, R2, R3 (2)

time

(h)

yieldb

(%)

1 Cr, Ph (1a) H, Ph, Ph (2a) 2 3a (71)

2 W, Ph (1b) 2a 0.5 3b (75)

3 1a H, Ph, 2-furyl (2b) 7 3c (68)

4 1b 2b 3 3d (66)

5 1a H, Ph, 2-thienyl (2c) 14 3e (61)

6 1a H, H, 2-thienyl (2d) 7 3f (62)

7 1b 2d 4 3g (78)

8 1b PhCONH, Ph, Ph (2e) 36 3h (51)

9 1b PhCONH, Ph, 2-furyl (2f) 28 3i (46)

10 1b PhCONH, Ph, 2-thienyl (2g) 19 3j (45)

11 1b PhCONH, Ph, 3-indolyl (2h) 21 3k (25)

12 Cr, TMS (1c) 2b 10 3l (60)

13 W, TMS (1d) 2b 8 3m (86)

14 Cr, p-tol (1e) 2b 8 3n (78)

15 W, p-tol (1f) 2b 4 3o (82)

aConditions: 1, 1.0 mmol; 2, 1.0 mmol; THF, 4 mL; 50 �C - reflux,atmospheric N2.

b Isolated yields. TMS = trimethylsilyl, p-tol =4-MeC6H4.

Scheme 1. Analogs of Penicillin and Cephalosporin Antibio-tics,2,3 and the Target Products in This Work

(7) For selected recent reports on [3þ 2] cycloaddition of azomethineimines and enones, see: (a) Altman, R. A.; Nilsson, B. L.; Overman,L. E.; de Alaniz, J. R.; Rohde, J. M.; Taupin, V. J. Org. Chem. 2010, 75,7519. (b) Sibi,M. P.; Rane,D.; Stanley, L.M.; Soeda, T.Org. Lett. 2008,10, 2971. (c) Chen,W.;Du,W.;Duan,Y.-Z.;Wu,Y.; Yang, S.-Y.; Chen,Y.-C. Angew. Chem., Int. Ed. 2007, 46, 7667.

(8) (a) Li, F. F.; Pinz�on, J. R.; Mercado, B. Q.; Olmstead, M. M.;Balch, A. L.; Echegoyen, L. J. Am. Chem. Soc. 2011, 133, 1563. (b) Biju,A. T.; Glorius, F. Angew. Chem., Int. Ed. 2010, 49, 9761.

(9) Roussi, F.; Bonin, M.; Chiaroni, A.; Micouin, L.; Riche, C.;Husson, H.-P. Tetrahedron Lett. 1999, 40, 3727.

(10) For selected recent reviews, see: (a) D€otz, K. H.; Stendel, J.Chem. Rev. 2009, 109, 3227. (b) Herndon, J.W.Coord. Chem. Rev. 2009,253, 86. (c) Sierra, M. A.; Fern�andez, I.; Cossıok, F. P.Chem. Commun.2008, 4671. (d) Kagoshima, H.; Fuchibe, K.; Akiyama, T. Chem. Rev.2007, 7, 104. (e) Sierra, M. A.; G�omez-Gallego, M.; Martınez-�Alvarez,R.Chem.;Eur. J. 2007, 13, 736. (f) Rosillo, M.; Domınguez, G.; P�erez-Castells, J.Chem. Soc. Rev. 2007, 36, 1589. (g) Barluenga, J.; Santamarıa,J.; Tom�as, M. Chem. Rev. 2004, 104, 2259.

(11) For selected reports, see: (a) Barluenga, J.; Aznar, F.; Palomero,M. A.Chem.;Eur. J. 2001, 7, 5318. (b) Barluenga, J.; Fern�andez-Marı,F.; Gonz�alez, R.; Aguilar, E.; Revelli, G. A.; Viado, A. L.; Fa~nan�as,F. J.; Olano, B. Eur. J. Org. Chem. 2000, 1773. (c) Yeung,M. L.; Li, W.-K.; Liu, H.-J.; Wang, Y.; Chan, K. S. J. Org. Chem. 1998, 63, 7670.

(12) (a) Baeza, B.; Casarrubios, L.; Ramırez-L�opez, P.; G�omez-Gallego, M.; Sierra, M. A. Organometallics 2009, 28, 956. (b) Sawoo,S.; Dutta, P.; Chakraborty, A.; Mukhopadhyay, R.; Bouloussa, O.;Sarkar, A. Chem. Commun. 2008, 5957. (c) Chan, K. S.; Wulff, W. D. J.Am. Chem. Soc. 1986, 108, 5229.

(13) (a) Barluenga, J.; Fern�andez-Marı, F.; Viado, A. L.; Aguilar, E.;Olano, B.; Garcıa-Granda, S.; Moya-Rubiera, C. Chem.;Eur. J. 1999,5, 883. (b) Barluenga, J.; Fern�andez-Marı, F.; Viado, A. L.; Aguilar, E.;Olano, B. J. Chem. Soc., Perkin Trans. 1 1997, 2267.

(14) Barluenga, J.; Fern�andez-Rodrıguez, M. A.; Aguilar, E.;Fern�andez-Marı, F.; Salinas, A.; Olano, B. Chem.;Eur. J. 2001, 7,3533.

(15) Zheng, Z. Y.; Yu, Z. K.; Luo, N.; Han, X. W. J. Org. Chem.2006, 71, 9695.

(16) Gopalsamuthiram, V.; Predeus, A. V.; Huang, R. H.; Wulff,W. D. J. Am. Chem. Soc. 2009, 131, 18018.

3386 Org. Lett., Vol. 13, No. 13, 2011

(entries 12�15). It is noteworthy that, in the reaction of 1cwith azomethine imine 2b, a desilylating product 3l0 wasalso isolated in 15% yield (eq 2).

Next, the reactionsof1withalkenyl azomethine imines 4were investigated (Table 2). Two new Fischer carbene

complex products 5a (45%) and 6a (53%) were isolated

from the [3þ 2] cycloaddition of 1awith 4a in THF under

heating conditions (entry 1). 5a is a pentacarbonyl carbene

complex featuring the same N,N-bicyclic core as 3 has,

while 6a is a tetracarbonyl carbene complex with Cr-πbonding. Under the same conditions, cycloaddition of 1b

with 4a afforded 5b (84%) as the only product (entry 2). A

remarkable metal effect led to the predominant formation

of products 5 (54�84%) from the reactions of tungsten

carbene complex 1bwith 4 (entries 2, 4, 8, and 10), whereas

increasing the steric hindrance on the bicyclic ring of

an azomethine imine substrate favored the formation of

products 6 (44�85%) from the reactions of 1a with 4

(entries 1, 3, 5�7, and 9).The characteristic 13C NMR signals of the carbene

carbons in complexes 3 and 5 appeared at 335.0�338.5ppm for CrdC and 305.5�310.3 ppm forWdC, and thoseof theM(CO)5moieties were shown at ca. 223/216 ppm forCr(CO)5 and ca. 202/197 ppm (1:4 intensity) for W(CO)5,

respectively. For tetracarbonyl carbene complexes 6, their13C NMR signals were situated in the region 320.8�321.6ppm for CrdC and 294.7�295.2 ppm forWdC, and thoseof the M(CO)4 moieties appeared as four discrete singletswith the same intensity at ca. 235/225/224/223 ppm forCr(CO)4 and ca. 216/210/205/203 ppm for W(CO)4, re-spectively, suggesting no CO exchange in the M(CO)4moieties in solution on the NMR time scale.The molecular structures of 3b and 6e were further

confirmed by X-ray crystallographic determinations (seethe Supporting Information (SI)), and their perspectiveviews are presented in Figure 1. Complex 3b exists as atypical pentacarbonyl carbene complex with a metal car-bene bond (W�C, 2.189(5) A), featuring an N,N-bicyclicpyrazolo-pyrazolone core. Complex 6e presents a molecu-lar structure containing the same N,N-bicyclic core as 3bhas, and its Cr�C bond length is 2.034(3) A. The bonddistance between the two alkenyl carbons coordinated tothe metal, i.e., C(8)�C(9) bond length in 6e, is 1.364(4) Awhich is longer than the commonCdCbond (ca. 1.34 A),16

and the distances between these vinylic carbons and themetal are 2.303(3) and 2.390(3) A, respectively, revealingπ-bonding between the metal and the CHdCH moiety.The molecular structures of 3b and 6e further confirmedthat R2 and R3 groups in the products are arranged syn toeach other. Because it is the δ-vinyl functional groupcoordinating to the metal in complex 6e instead of theβ-vinyl moiety coordinating to the metal as reported inBarluenga’s constrained tetracarbonyl complexes,17 com-plexes 6 are stable in the solid state or solution.Interconversion between complexes 5 and 6 was inves-

tigated to explore their stability. Heating in vacuo (ca 1mmHg) made most of the pentacarbonyl carbene com-plexes 5 decompose to the corresponding tetracarbonylcarbene complexes 6 (see the SI). For example, 5a and 5c

were quantitatively converted to 6a and 6c upon heating at

50 �C/1mmHg for 8 h, respectively. Partial decomposition

of 5hand 5joccurred in vacuo after heating at 90 �C for 8 h,

resulting in their corresponding tetracarbonyl complexes

6h and 6j in ca. 50% yields, while 5b and 5d withstood the

heating conditions, exhibiting very high stability. However,

Figure 1. Molecular structures of 3b and 6e.Table 2. [3 þ 2] Cycloaddition of Alkenyl Azomethine Imines 4with 1a

entry 1 R1, R2, R4

time

(h)

yieldb

(%)

1 1a H, H, Ph (4a) 1 5a (45) 6a (53)

2 1b 4a 0.3 5b (84) 6b (�)

3 1a H, H, 2-furyl (4b) 2 5c (37) 6c (57)

4 1b 4b 1 5d (79) 6d (�)

5 1a H, Ph, Ph (4c) 1 5e (�) 6e (75)

6 1b 4c 0.5 5f (74) 6f (�)

7 1a H, Ph, 2-furyl (4d) 2 5g (�) 6g (85)

8 1b 4d 1 5h (85) 6h (�)

9 1a PhCONH, Ph, Ph (4e) 4 5i (�) 6i (44)

10 1b 4e 3 5j (63) 6j (18)

11 1a PhCONH, Ph, 2-furyl (4f) 4 5k (�) 6k (52)

12 1b 4f 4 5l (54) 6l (14)

aReaction conditions: 1, 1.0 mmol; 4, 1.0 mmol; THF, 4 mL; 50 �C -reflux, atmospheric N2.

b Isolated yields.

(17) Barluenga, J.; Aznar, F.; Martın, A.; Garcıa-Granda, S.; P�erez-Carre~no, E. J. Am. Chem. Soc. 1994, 116, 11191.

Org. Lett., Vol. 13, No. 13, 2011 3387

conversion of 6 to 5 took place undermild conditions. In thepresence of atmospheric CO, violet 6a was quantitativelyconverted to orange 5a in dichloromethane at ambienttemperature over a period of 24 h. Upon exposure of 6c,6g, and 6i to a CO atmosphere, they were only partiallyconverted to the corresponding pentacarbonyl analogues 5c,5g, and5i in 50�80%yields. It shouldbenoted that6hand6iwere unreactive with CO and stayed unchanged in THFunder the CO atmosphere at 50 �C over a period of 20 h.These results suggest that the present tetracarbonyl carbenecomplexes 6 are much more stable than those tetracarbonylaminovinylcarbene complexes reported by Barluenga et al.17

Demetalation of the newly formed Fischer carbenecomplexes was carried out in dichloromethane or THFat 0�40 �C by using pyridine-N-oxide (PNO) as theoxidant.18 Thus, oxidative demetalation of 3 with PNOafforded N,N-bicyclic pyrazolidin-3-ones 7a�h in41�84% yields, and that of 5 and 6 produced the sametype of organic products 8a�f in 40�81%yields (Figure 2).Itwas found that complexes 6 are less reactive toPNOthantheir corresponding pentacarbonyl analogs 5 and theiroxidative demetalation should be carried out at 40 �C.Ceric ammonium nitrate (CAN) also showed potential in

oxidatively demetalating these Fischer carbene complexes.Subsequently, oxidativedemetalationof 5b, 5d, and 5fwithCAN led to cleavage of their amide C�N bonds, formingthe ring-opening products, i.e., tetrasubstituted pyrazoles9a�c (75�90%) (eq 4). In a similar fashion, oxidation ofthe fully substituted pyrazolo-pyrazolone Fischer carbenecomplexes 5j and 5l with CAN efficiently afforded cyclo-prop-2-enone 10 (92�94%) and trisubstituted 1H-pyra-zoles 11 (eq 5). Formation of 10 is presumably attributedto sequential C�N bond cleavages and intramolecularcarbon�carbon coupling in 5. These results suggest apromising route to multisubstituted pyrazoles for bio-chemical purposes.3,9

In summary, regioselective [3 þ 2] annulation of azo-methine imines with 1-alkynyl Fischer carbene complexeshas been successfully developed to synthesize versatilefunctionalizedN,N-bicyclic pyrazolidin-3-ones. A remark-able metal effect was found to direct formation of thepentacarbonyl and tetracarbonyl carbene complexes fromthe reactions of alkenyl azomethine imines with 1-alkynylFischer carbene complexes. Oxidative demetalation ofthe newly formed N-heterocyclic carbene complexesaffordedN,N-bicyclic pyrazolidin-3-ones by using pyr-idine-N-oxide and produced cycloprop-2-enone andmultisubstituted pyrazoles with ceric ammonium nitrateas the oxidant. These results suggest a novel alternativeroute to potentially bioactive functionalized N,N-bicyclicpyrazolidin-3-ones, cycloprop-2-enone, and functiona-lized pyrazoles under mild conditions.

Acknowledgment. We are grateful to the National Nat-ural Science Foundation of China (20772124, 20972157),973 Program (2009CB825300), Natural Science Founda-tion of Liaoning Province (20102225), and the InnovationProgram of CAS (DICP K2009D04) for support of thisresearch.

Supporting Information Available. Experimental proce-dures, analytical data andcopiesofNMRspectra, andX-raycrystallographic files for 3b and 6e. Thismaterial is availablefree of charge via the Internet at http://pubs.acs.org.

Figure 2. Oxidative demetalation of complexes 3, 5, and 6.

(18) (a) Zheng, Z. Y.; Chen, J. Z.; Luo, N.; Yu, Z. K.; Han, X. W.Organometallics 2006, 25, 5301. (b) Zheng, Z. Y.; Chen, J. Z.; Yu, Z. K.;Han, X. W. J. Organomet. Chem. 2006, 691, 3679.